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Diabetes Volume 65, July 2016 1757

Deborah E. Sellmeyer,1 Roberto Civitelli,2 Lorenz C. Hofbauer,3 Sundeep Khosla,4


Beata Lecka-Czernik,5 and Ann V. Schwartz6

Skeletal Metabolism, Fracture Risk,


and Fracture Outcomes in Type 1 and
Type 2 Diabetes
Diabetes 2016;65:17571766 | DOI: 10.2337/db16-0063

Fracture risk is signicantly increased in both type 1 and approximately 29% of hip fracture patients never return to
type 2 diabetes, and individuals with diabetes experience their prefracture status for activities of daily living (4). Ex-
worse fracture outcomes than normoglycemic indivi- tended recovery time and disability are also common after a
duals. Factors that increase fracture risk include lower vertebral fracture.
bone mass in type 1 diabetes and compromised skeletal Individuals with diabetes are at higher fracture risk and

PERSPECTIVES IN DIABETES
quality and strength despite preserved bone density in have even worse fracture outcomes than normoglycemic
type 2 diabetes, as well as the effects of comorbidities individuals. However, strategies to reduce fracture risk
such as diabetic macro- and microvascular complications. appear underutilized in this population, possibly related
In this Perspective, we assess the developing scientic to challenges of identifying high-risk patients and con-
knowledge regarding the epidemiology and pathophysiol-
cerns regarding effective treatments for prevention. The
ogy of skeletal fragility in patients with diabetes and the
pathophysiology of increased skeletal fragility is complex,
emerging data on the prediction, treatment, and outcomes
differs between T1D and T2D, and is the subject of intense
of fractures in individuals with type 1 and type 2 diabetes.
investigation. In this Perspective, we review the current
knowledge regarding the epidemiology and pathophysiol-
ogy of diabetes-induced bone disease. We also discuss
Fractures are a signicant health issue for patients with
current issues pertaining to the prediction, treatment, and
diabetes. In type 1 diabetes (T1D), improvements in life
outcomes of fractures in individuals with T1D and T2D.
expectancy are increasing the number of patients who are
living to older age. In addition, over a quarter of adults
aged 65 years and older in the U.S. have type 2 diabetes EPIDEMIOLOGY OF FRACTURES IN INDIVIDUALS
(T2D). In this older age-group, fractures are a common WITH T1D AND T2D
event; a 60-year-old white woman has a 44% probability Individuals with T1D have double the risk of any fracture
of having at least one fracture in her remaining lifetime (1). and four to ve times higher hip fracture risk compared
The cost of treating fractures in the U.S. exceeded $17 billion with those without diabetes (5). Higher fracture risk in
in 2005 and is predicted to increase by 50% by 2025 (2). T1D is evident in childhood and extends throughout the
Importantly, hip fractures result in a very high risk of life span, affecting both sexes similarly. T1D is character-
mortality and disability. Mortality rates increase ve- to ized by modest decits in bone mineral density (BMD)
eightfold in the 3 months following a hip fracture and that account for some, but not all, of the increased fracture
remain elevated even 5 years after fracture (3). Furthermore, risk (6). Reduced bone quality also appears to contribute to

1Division of Endocrinology, Diabetes, and Metabolism, Johns Hopkins University 5 Departments of Orthopaedic Surgery and Physiology and Pharmacology and
School of Medicine, Baltimore, MD Center for Diabetes and Endocrine Research, The University of Toledo Col-
2Division of Bone and Mineral Diseases, Washington University in St. Louis lege of Medicine and Life Sciences, Toledo, OH
School of Medicine, St. Louis, MO 6 Department of Epidemiology & Biostatistics, University of California, San
3Department of Medicine III and Center for Healthy Aging, Technische Francisco, San Francisco, CA
Universitt Dresden, Germany and Center for Regenerative Therapies Dresden, Corresponding author: Deborah E. Sellmeyer, dsellme1@jhmi.edu.
Dresden, Germany
4Division of Endocrinology, Diabetes, Metabolism, and Nutrition Research Received 13 January 2016 and accepted 23 March 2016.
and the Robert and Arlene Kogod Center on Aging, Mayo Clinic, Rochester, 2016 by the American Diabetes Association. Readers may use this article as
MN long as the work is properly cited, the use is educational and not for prot, and
the work is not altered.
1758 Fracture Risk and Outcomes in T1D and T2D Diabetes Volume 65, July 2016

increased fracture risk in T1D, as discussed later. In con- The World Health Organization Fracture Risk Assess-
trast, T2D is associated with overweight and higher bone ment Tool (FRAX) takes into account additional risk factors
density, factors that are associated with lower fracture risk besides BMD in fracture prediction, including age, sex, race,
in normoglycemic individuals. However, among older adults BMI, previous fracture, parental history of hip fracture,
with T2D, the risk of hip fracture is increased 4070% smoking, alcohol consumption, rheumatoid arthritis, and
compared with normoglycemic individuals (6,7). Among in- use of glucocorticoids. Glucocorticoid use in particular is
dividuals over the age of 65 years participating in the National higher among those with T2D. However, even with these
Health and Nutrition Examination Survey (NHANES), the additional risk factors taken into account, FRAX underes-
risk of any fracture in non-Hispanic white adults was timates fracture risk in patients with T2D; it has been
similar in those with and without diabetes, as assessed calculated that the effect of diabetes on FRAX estimated
by self-report or HbA1c $6.5% (hazard ratio [HR] 1.17 fracture risk is equivalent to adding 10 years of age (18).
[95% CI 0.891.52]) (8). Given the age at diabetes diag- Traditional risk factors for fracture, including lower
nosis and use of insulin, it was estimated that 97% of BMD, older age, female sex, and glucocorticoid use, predict
participants had T2D in this analysis. Risks were higher fractures in patients with diabetes (5,19). In addition, in
compared with non-Hispanic black (HR 1.86 [95% CI patients with T2D, longer duration of diabetes and poor
1.053.30]) and Mexican American (HR 2.29 [95% CI glycemic control are each associated with higher fracture
1.413.73]) adults without diabetes. Higher fracture risk risk (2024). Among participants with diabetes in a U.S.
does not appear to extend to those with prediabetes, de- cohort, those with baseline HbA1c .8% had a 1.63 (95%
ned by fasting glucose or 2-h glucose (8,9). CI 1.092.44) higher rate of any fracture than those with
Individuals with either T1D or T2D, particularly those lower HbA1c (23). Recent evidence suggests that poor
with diabetes complications, are more likely to experience glycemic control is a risk factor for fracture in T1D as
delayed healing and postsurgical complications, such as well (5). There is evidence that microvascular complica-
wound infection (1014). Mortality following hip frac- tions (5,25), stroke, and cardiovascular disease (26) are
ture is 1.44 times higher in those with diabetes (15). also risk factors for fracture in T1D and T2D, although
Several large case-control studies among individuals ad- current data are limited (25).
mitted with hip fractures have shown an increased risk The majority of fractures in older adults are the result
of postoperative cardiac events among those patients of a fall with relatively modest trauma. Evidence regard-
with diabetes and an increased length of stay of 14 ing falls in patients with T1D is lacking, but a recent
days (10,16,17). meta-analysis reported a modestly increased rate of falls
Prediction of fracture risk in patients with T2D is in patients with T2D (HR 1.19 [95% CI 1.081.31]), with
challenging. Older adults with T2D have fractures at a an even higher fall rate in insulin-treated patients with
higher bone density than individuals who do not have di- T2D (27). Although the increased propensity for falling
abetes. As a result, while lower BMD does predict fracture likely contributes to the increased fracture risk at a given
risk in patients with diabetes, the BMD T-score underesti- BMD, observational studies have found that falls do not
mates fracture risk (18) (Fig. 1). For example, hip fracture fully account for the increased risk in T2D (9,21,28,29),
risk in a woman with diabetes and a femoral neck BMD suggesting that reduced bone quality is an important con-
T-score of 21.9 is similar to the risk in a normoglycemic tributor. This epidemiological evidence is limited by the
woman of the same age with a T-score of 22.5. imprecision in measuring fall frequency by self-report.

Figure 1Femoral neck BMD T-score and 10-year fracture risk at age 75 years by diabetes status and insulin use. Estimated 10-year
cumulative fracture risk at age 75 years in men and women, calculated using the Cox proportional hazards regression model baseline
survival function raised to the power of the relative hazard for each combination of diabetes group and T-score. DM, diabetes. Adapted with
permission from Schwartz et al. (18).
diabetes.diabetesjournals.org Sellmeyer and Associates 1759

Rodent models of diabetic bone, discussed below, provide substantial microarchitectural abnormalities, including lower
another indication that bone quality is reduced in diabetes. trabecular thickness and estimated bone strength and
greater trabecular separation and network inhomogeneity
PATHOGENESIS OF T1D EFFECTS ON THE compared with patients without microvascular disease
SKELETON (36). Bone microarchitecture in the T1D patients without
Determinants of Reduced Bone Strength in T1D evidence of microvascular complications did not differ
The pathogenesis of impaired bone strength and increased from those without diabetes (35,36).
fragility fractures in T1D is not fully understood. Skeletal
Alterations at the Bone Cell and Tissue Level
health in this condition is highly variable and, as in
Rodent models of T1D do not fully recapitulate the bone
normoglycemic individuals, depends on physical activity,
alterations seen in humans; however, such models are
lifestyle, and genetic factors. The age at diagnosis of T1D,
useful to study the interactions between bone and energy
disease duration and control, and the presence of micro-
metabolism. Commonly used models include the two
vascular complications affect bone mass and strength (30).
spontaneous NOD mice (37,38) and BioBreeding diabetes-
Patients with T1D onset at childhood, i.e., before the peak
prone rats (39), as well as streptozotocin-induced diabetes
bone mass is acquired, have a BMD measured by DXA that
in rats and mice (37,40,41). Studies in these animals con-
is, on average, 0.51.0 SD lower (30). Moreover, bones in
sistently demonstrate reduced trabecular and cortical bone
children with T1D tend to be smaller, translating into an
mass, reduced bone formation rate, and low bone turnover
unfavorable geometry to resist fractures. These bone
based on gene expression and histomorphometry analysis,
remodeling defects have been linked to a relative lack of
possibly the result of increased oxidative stress. Insulin-
the anabolic effects of insulin on osteoblastic bone forma-
treated animals showed no differences compared with con-
tion (31) and alterations of the growth hormone/IGF-I
trol animals. Rodent models of diabetes also show a greater
axis as a result of poor metabolic control (32). However,
accumulation of AGEs in bone collagen, resulting in alter-
bone size may only be transiently decreased; among
ations in the material properties of the bone (42).
10-year-old children with T1D with a duration of 4 years,
In vitro, high glucose levels and AGEs suppress bone
bone size was normal 5 years later (33). The exact bio-
formation by increasing sclerostin expression in osteo-
logical basis underlying this vulnerable phase for bone
cytes and AGEs inhibit bone resorption by decreasing
development in some children with T1D is unclear.
RANKL expression; both effects can be prevented by
In adults with T1D, most studies indicate a BMD of
pretreatment with parathyroid hormone (43). Osteoblast
approximately 0.51.0 SD below subjects without diabetes
function has been shown to depend on glucose uptake via
of the same age, i.e., a Z-score of 20.5 to 21.0 when bone
the transporter GLUT1, whose expression precedes that
density is measured by DXA. Although the duration of the
of Runx2, the earliest osteoblast transcription factor (44).
disease or HbA1c level was not commonly associated with
In the absence of normal glucose uptake, Runx2 does not
low BMD, diabetic polyneuropathy, retinopathy, and ne-
induce osteoblast differentiation, whereas increased se-
phropathy have been consistently linked to lower BMD in
rum glucose levels rescue osteoblast functions in Runx2
T1D (30). Trabecular bone score, an indirect assessment
deciency (44).
of bone microarchitecture derived from DXA scans, has
In humans, T1D is associated with lower serum levels
also been shown to be lower in patients with T1D with
of bone formation markers and vitamin D and results for
vertebral fractures (34).
bone resorption markers are equivocal (45). In contrast, a
Lower BMD is an important contributing factor to
histomorphometry study of iliac crest biopsies found no
fracture risk in T1D; however, the relatively modest
major differences in bone formation rates, comparing 18
reduction in BMD relative to normoglycemic individuals
otherwise healthy patients with T1D and age- and sex-
does not fully account for the increased fracture risk in
matched control subjects (46). However, this study only
patients with diabetes (6), suggesting that other aspects
included T1D patients without any evidence of microvas-
of bone quality not captured by DXA are compromised in
cular or macrovascular complications. Patients with T1D
T1D. Hypothesized mechanisms for reduced bone quality,
and a history of fracture showed subtle abnormalities in
in both T1D and T2D, include direct effects of hypergly-
bone microarchitecture by microcomputed tomography
cemia on bone cells, accumulation of advanced glycation
and dynamic histomorphometry. In these T1D patients
end products (AGEs) in bone collagen, and damage to
with fractures, the presence of pentosidine, an AGE, in
bone vasculature.
the bone matrix, along with a higher degree of mineraliza-
Two recent studies have linked microvascular disease
tion, was associated with a reduced modulus of elasticity,
to altered bone microarchitecture measured with high-
thus rendering the bone less exible (47). In a separate
resolution peripheral quantitative computed tomography
study, serum levels of pentosidine were associated with
(HR-pQCT) in T1D. Bone volume/total volume of the
prevalent fractures in T1D independently of BMD (48).
proximal tibia was lower in subjects with T1D and reti-
nopathy was associated with lower serum IGF-I levels Bone Vasculature in Diabetes
(35). Similarly, patients with T1D and retinopathy dis- Bone vasculature is critical for bone growth, remodeling,
played lower total and trabecular volumetric BMD and and fracture healing as it provides sustained blood supplies
1760 Fracture Risk and Outcomes in T1D and T2D Diabetes Volume 65, July 2016

of oxygen, nutrients, and regulatory factors and removal of combined with the negative effects of longer duration of
metabolic waste. Bone receives up to 10% of cardiac output, diabetes, including the development of microvascular com-
which is distributed within the mineral compartment and plications and accumulation of AGEs. In prediabetes and
the bone marrow by a complex system of sinusoid and classic newly diagnosed diabetes, positive effects predominate,
capillaries. Vasculature also provides a niche for the devel- whereas with longer duration of diabetes, the negative
opment of osteoblast progenitors, and capillaries present effects become increasingly signicant.
in Haversian canals deliver osteoclasts and are a source of
Bone Turnover in T2D
skeletal stem cells (pericytes) (49). The vascular compli-
Similar to T1D, most studies have reported reductions in
cations in diabetes include impairment in endothelium- biochemical markers of bone formation and bone re-
dependent vasodilation, vascular calcication, and defective
sorption in patients with T2D (45). Whether there is a
angiogenesis, and it is conceivable that the same patholog-
disproportionate reduction in bone formation relative to
ical changes develop in bone. Thus, reduction in bone and
bone resorption remains unclear. A potential limitation
marrow blood ow and impairment in new vessel formation
with the use of serum markers of bone resorption (e.g.,
may have signicant consequences for the osteoblast-
serum COOH-terminal telopeptide of type I collagen) in
dependent hematopoietic niche and decrease bone remod-
patients with diabetes is that, based on animal data, di-
eling activity, consequently decreasing bone quality and
abetes may be associated with a reduction in enzymatic
delaying fracture healing. cross-links, leading to an underestimation of the bone
Direct studies of diabetes and bone vasculature in humans
resorption rate (42). Although bone histomorphometry
are not available. However, indirect evidence provides some
remains the denitive approach to assess bone remodel-
intriguing clues that vascular damage may be an important
ing, bone biopsy studies in T2D patients are sparse and
component of diabetic bone disease in both T1D and T2D.
have examined relatively small numbers of subjects. Sig-
As discussed earlier, decits in bone microarchitecture are
nicantly reduced indices of bone formation were found
associated with microvascular complications. The hip is
among 8 subjects with diabetes (2 with T1D and 6 with
particularly prone to fractures in T1D, which may be
T2D) as compared with 23 control subjects (52). Data on
related to the peculiar vascular supply of the femoral head bone resorption were not explicitly provided in this re-
by an end artery (A. capitis femoris). In addition, micro-
port, though Krakauer et al. (52) commented that eroded
vascular complications are associated with lower BMD (30)
surface was high-normal but osteoclast surface was low-
and fracture risk in those with T1D (5).
normal (data not shown), probably reecting prior re-
sorptive activity that was not followed by formation.
PATHOGENESIS OF T2D EFFECTS ON THE
SKELETON In another study, reduced dynamic indices of bone for-
mation (bone formation rate and osteoblast numbers/bone
BMD in T2D
surface) were found in 5 subjects with T2D relative to 4
As reviewed earlier, fracture risk is increased in patients control subjects (53). Eroded surfaces and osteoclast num-
with T2D despite preserved or even increased BMD by
bers/bone surface did not differ between the T2D and control
DXA. A meta-analysis reported high Z-scores of 0.41 at
subjects. Thus, bone formation appears to be reduced in T2D
the spine and 0.27 at the hip in patients with T2D, pri-
patients, while data regarding bone resorption are less clear.
marily associated with the higher BMI in these patients
Increased serum sclerostin, which inhibits bone for-
(6). Data from a cohort of Chinese postmenopausal women
mation, has been reported in patients with T2D relative
with T2D showed that although obese patients with diabe-
to control subjects (54,55); however, the role of sclerostin
tes and control subjects had similar BMD T- and Z-scores
in mediating impaired bone formation in T2D remains to
at various skeletal sites, nonobese women with T2D had be established.
lower BMD than control subjects matched on BMI (50).
Even though obese patients with T2D have increased Bone Quality in T2D
BMD by DXA, there is evidence that older white women, Considering that BMD by DXA is preserved, other com-
but not men or black women, with diabetes have more ponents of skeletal strength generally categorized as bone
rapid bone loss at the femoral neck and total hip (51). In quality may be abnormal in T2D patients. As high glu-
part, this was associated with weight loss over time in the cose levels lead to the accumulation of AGEs in the
white women, which did not occur in men or black women. organic bone matrix by nonenzymatic glycation, it is
However, the association between T2D and bone loss per- possible that the accumulation of AGEs in bone leads
sisted at the femoral neck in white women even after to impaired biomechanical properties in T2D patients
adjusting for weight loss. Thus, despite having higher base- (56). Support for this hypothesis comes from studies
line BMD, white women with T2D have increased rates of showing that urinary pentosidine is associated with in-
bone loss, particularly at the femoral neck, which may con- creased fracture incidence in T2D patients (57) and that
tribute to their increase in fracture risk. This seemingly serum pentosidine is increased in T2D patients with ver-
contradictory nding of higher cross-sectional BMD with tebral fractures (58). Thus, the accumulation of AGEs may
more rapid bone loss may reect the net result of the pos- be a common pathophysiological mechanism of reduced
itive effects of overweight and hyperinsulinemia on bone bone quality in T1D and T2D.
diabetes.diabetesjournals.org Sellmeyer and Associates 1761

Further supporting the notion of defective bone quality insulin receptors, and animal studies imply that increased
(and strength) in T2D, one study using HR-pQCT (59) insulin signaling correlates positively with bone turnover
demonstrated that cortical porosity was markedly in- and bone formation, whereas insulin resistance attenuates
creased (by 124%) in 19 T2D postmenopausal women bone remodeling (62,63). Bone dependence on insulin and
relative to an equal number of control subjects without glucose metabolism poses the question as to whether bone
diabetes (59) (Fig. 2). None of the trabecular parameters develops insulin resistance and whether such resistance is
(e.g., trabecular bone volume fraction, trabecular number manifested with decreased bone turnover. Clarication of
or thickness) differed between the T2D and control sub- this issue may have signicant implications for the devel-
jects. An increase in cortical porosity, albeit of lesser mag- opment of therapies to treat diabetic bone disease associ-
nitude (26%), was also reported in 22 African American ated with low bone turnover.
women with T2D relative to 78 control women (60), again
Bone and Fat Relationships in T2D
with no signicant differences in trabecular parameters.
Impairment in adipose tissue function is one of the conse-
Thus, increased cortical porosity, an element of bone qual-
quences of T2D that directly affects carbohydrate and lipid
ity not assessed by DXA, may contribute to increased
metabolism and insulin sensitivity. Increase in visceral
fracture risk in T2D patients.
adiposity, which relates to increased inammation and
In addition to bone microarchitecture, the material
metabolic syndrome, is negatively associated with lumbar
properties of bone also contribute to bone quality. Recently, volumetric BMD (64) and with bone volume and bone
microindentation of the cortex has gained acceptance as
formation in iliac crest biopsies from premenopausal
a research tool for estimating bone material strength in
women (65). Fat inltration in muscles is increased in
humans. Following local anesthesia, this device creates
diabetes and is associated with incident fractures, al-
microindents over the shaft of the tibia, which provides a
though this association does not account for the higher
measure of bone material strength (bone material strength
fracture risk in diabetes (66). Diabetes is associated with
index [BMSi]). This technique (61) showed that postmen-
higher marrow fat in rodent models, although denitive
opausal women with T2D have signicant reductions in
human studies are lacking (37,67). Increased marrow ad-
BMSi as compared with control subjects without diabetes iposity and decreased levels of unsaturated fatty acids
(Fig. 3). This study also found that HbA1c levels were
in the bone marrow correlate positively with fractures
inversely correlated with BMSi in the T2D patients, sug-
(68,69). Marrow adipose tissue accumulates in long bones
gesting that the abnormal bone material properties in
and vertebrae and constitutes up to 10% of total body
these patients may be related to chronic hyperglycemia,
fat. Marrow adipose tissue is both unique and similar to
perhaps mediated by AGEs.
extramedullary fat in respect to origin, metabolism, and
Bone Turnover and Insulin Signaling function and possesses characteristics of both white and
Hyperinsulinemia and hyperglycemia may affect bone beige fat (70). Studies in rodents show that the beige
remodeling by either directly modulating activities of phenotype, which is characterized by the production of
bone cells or changing the milieu of the bone marrow en- bone anabolic factors, is attenuated with diabetes despite
vironment. Osteoblasts, osteoclasts, and osteocytes express an expansion of this fat depot (71).

Figure 2Median (by total volumetric BMD) HR-pQCT images of the distal radius from control (top) and T2D (bottom) subjects: distal-most
slices (A and E), proximal-most slices (B and F), three-dimensional visualization of the mineralized bone structure (C and G), and three-
dimensional visualization of cortical bone (transparent gray) and cortical porosity (dark gray dots) (D and H). Reprinted with permission from
Burghardt et al. (59).
1762 Fracture Risk and Outcomes in T1D and T2D Diabetes Volume 65, July 2016

Figure 3Unadjusted (A) and BMI-adjusted (B) comparisons of bone material strength between patients with T2D and age-matched
control subjects without diabetes. Values are shown as mean 6 SE. P < 0.001. Reprinted with permission from Farr et al. (61).

Bone and Antidiabetes Medications an increased risk of falls and fractures. Additionally, poor
As bone is involved with energy metabolism, it can be a target glycemic control, generally dened as an HbA1c value .8%,
for certain antidiabetes therapies (72). Thiazolidinediones has been shown to increase fracture risk; however, the
(TZDs), high-afnity ligands and activators of peroxisome fracture benets of reducing HbA1c levels to lower levels
proliferatoractivated receptor g, target hematopoietic have not been established. In randomized trials among
and mesenchymal cells in the bone marrow, resulting in individuals with T2D, neither intensive glycemic control
unbalanced bone remodeling with high bone resorption and (median HbA1c 6.4% in the intensive group vs. 7.5% in
low bone formation and consequent bone loss and accumu- the standard glycemic control group) nor intensive blood
lation of large quantities of fat in the bone marrow cavity. pressure control affected the risk of falls or fractures,
Increased bone loss at the lumbar spine, total hip, and either positively or negatively (76,77). Although there is
femoral neck in women on TZD therapy emerged in the limited evidence that improved glycemic control may pre-
recent meta-analysis of 10 randomized clinical trials (73). vent bone loss in T1D (78), signicant hypoglycemia has
Therapy with either rosiglitazone or pioglitazone also in- been associated with increased fracture risk in T1D and
creased fracture risk by approximately twofold in women, T2D, possibly related to falls in the older population (79,80).
but not in men. Risk appeared to increase with duration Glycemic control following current guidelines may be
of treatment. helpful to prevent complications, removing the contribu-
Recently, a novel class of antidiabetes medications, tion of hyperglycemia and diabetes complications to in-
sodiumglucose cotransporter 2 inhibitors, has been scru- creased fracture risk; however, hypoglycemia should be
tinized by the U.S. Food and Drug Administration for a avoided, particularly in older individuals. The evidence
potential harmful effect on bone. It has been reported that TZDs increase fracture risk in postmenopausal women
that patients receiving canagliozin have an increased is robust, and these agents should be avoided in postmen-
fracture rate as early as 12 weeks after initiating therapy opausal women with T2D.
(74). However, there was no difference in fracture rates
for empagliozin (75). The bone risk associated with Prevention of Postfracture Complications in Patients
sodiumglucose cotransporter 2 inhibitor therapy may in- With Diabetes
clude alterations in calcium and phosphate homeostasis Animal studies demonstrate reduced rates of cellular dif-
or more direct effects on cells involved in bone remodel- ferentiation, delayed callus formation, and slowed miner-
ing owing to the glucose dependence of their metabolism. alization after fracture in diabetic animals (8183). Tight
There is no evidence for negative effects on bone of other glycemic control and local insulin infusion improve these
antidiabetes therapies, including biguanides, glucagon-like bone properties in animals (84,85). In humans, higher
peptide 1 analogs, and dipeptidyl peptidase 4 inhibitors; HbA1c levels at the time of surgery for ankle fracture and
in fact, some of these therapies may even be protective within 3 months postoperatively have been associated with
against fractures (72). an increased risk of infection, delayed union, malunion,
and nonunion among patients with T1D or T2D (13,86).
MANAGEMENT OF LOW BONE MASS AND Although a baseline and postoperative HbA1c level ,7%
FRACTURE PREVENTION appears to be benecial in several reports, data are not
Effects of Diabetes Complications and Improving available on the optimal level of glycemic control in pa-
Glycemic Control as a Means to Reduce Fracture Risk tients with diabetes with fractures. Until such data are
Diabetic microvascular complications, such as neuropathy, available, current guidelines for inpatient and outpatient
nephropathy, and retinopathy, have been associated with glycemic control should be followed.
diabetes.diabetesjournals.org Sellmeyer and Associates 1763

Nutrition and Lifestyle Interventions to Reduce unclear. The roles of hyperglycemia, AGEs, and damage to
Fracture Risk bone vasculature are current areas of research. Increased
Age-appropriate intakes of calcium and vitamin D should falls also contribute to the higher fracture risk. Improved
be ensured in all individuals with diabetes. Calcium intake glycemic control may reduce fracture risk and is impor-
and calcium supplements are not associated with the amount tant to fracture healing but must be balanced against
of calcied plaque in the carotid, coronary, or aortic arteries negative effects of hypoglycemia. Nutrition and lifestyle
in individuals with T2D (87). Weight-bearing physical ac- measures to improve bone health are appropriate for
tivity increases bone density in children with T1D to a individuals with diabetes, and osteoporosis medications
degree similar to that in normoglycemic children (88). As- have generally proven to be equally effective in patients
sessment of fall risk and appropriate fall prevention mea- with diabetes compared with euglycemic individuals. Initi-
sures should be included in the care of older patients with ation of osteoporosis medications in patients with diabetes
diabetes. Among overweight adults with T2D, signicant with low bone density or low-trauma fracture is appro-
weight loss may result in bone loss, although the magnitude priate. More data are needed on identifying patients with
of bone loss appears to be small (less than 1% at 4 years), diabetes with normal bone density and no history of frac-
was seen only in men, and fracture rates were not increased ture who will benet from treatment with osteoporosis
(89,90). The optimal exercise regimen for weight reduction medications to prevent fractures. If patients with diabetes
in individuals with diabetes while minimizing bone loss has develop renal insufciency, particularly when estimated
not been determined. glomerular ltration rate is below 30 mL/min or the patient
undergoes transplantation, additional considerations with
Effect of Osteoporosis Therapies in Patients With respect to renal-related metabolic bone disease or gluco-
Diabetes corticoid treatment also need to be addressed. Although
As discussed earlier, serum markers of bone turnover are skeletal health in T1D and T2D is an area of very active
generally lower in patients with T1D and T2D than in investigation, much remains to be learned regarding the
normoglycemic individuals, raising the concern that anti- pathophysiology of increased fracture risk, how to estimate
resorptive agents used as osteoporosis therapy may further fracture risk, and effective strategies to reduce fracture risk
exacerbate an already decreased remodeling state rather in patients with diabetes.
than provide a protective skeletal effect. However, registry
data and data from clinical trials of osteoporosis medica-
tions support the effectiveness of these agents in individ- Funding. L.C.H. received grant support from Deutsche Forschungsgemeinschaft
uals with diabetes. Alendronate increased bone density Sonderforschungsbereiche/Transregio 67 (Project B2). S.K. received grant support
in 297 women with diabetes enrolled in the Fracture from the National Institutes of Health (AG004875 and AR027065). B.L.-C. received
Intervention Trial (FIT) equivalently to normoglycemic grant support from the American Diabetes Association (7-13-BS-089).
individuals (91). Raloxifene reduced the risk of vertebral Duality of Interest. D.E.S. is a member of Data Safety Monitoring Board
fracture risk by 35% in the Raloxifene Use for The Heart for Amgen. R.C. received research support from Amgen and has stock ownership
in Amgen, Eli Lilly, and Merck & Co. A.V.S. received a speaker honorarium from
(RUTH) trial, with consistent effects among subgroups
Chugai Pharmaceutical Co. and served on an advisory board for Janssen Phar-
including the approximately 4,500 women with diabetes
maceuticals. No other potential conicts of interest relevant to this article were
(92). Examination of osteoporosis medication use and frac-
reported.
tures in the Danish Registry demonstrated no difference in
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